This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Our laboratory is interested in elucidating the mechanism of signaling transduction in the pathway of apoptosis and inflammation. These pathways are crucial for mammalian biology including immune regulation and cellular homeostasis. Malfunction of these pathways can lead to serious human diseases such as cancer, autoimmune diseases and degenerative diseases. One major aspect of our studies has to do with the inhibition and activation of caspases, a family of cysteine proteases that execute apoptosis. This study seeks to determine crystal structures of caspase activating complexes and caspases in complex with natural protein inhibitors or small molecule inhibitors. Another aspect of our studies deals with the pathway for NF-kappaB activation and the induction of inflammatory responses through innate immunity. We seek to determine crystal structures of complexes of ubiquitin ligases, kinases and other effectors. To fully understand the molecular mechanisms, we complement the structural studies with biochemical, biophysical and cell biological studies, some of which are in collaboration with leaders in the field.